Selected Abstracts

Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2001R. Gerlai
Abstract
Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models.
However, a role for endogenous GDNF in brain function has not been established.
Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied.
Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function.
While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze.
A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit.
These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities.
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Role of activity-dependent mechanisms in the control of dopaminergic neuron survival

JOURNAL OF NEUROCHEMISTRY, Issue 2 2007Patrick P. Michel
Abstract
Dopaminergic neurons that constitute the nigrostriatal pathway are characterized by singular electrical properties that allow them to discharge in vivo spontaneously in a spectrum of patterns ranging from pacemaker to random and bursting modes.
These electrophysiological features allow dopaminergic neurons to optimize the release of dopamine in their terminal fields.
However, there is emerging evidence indicating that electrical activity might also participate in the control of dopaminergic neuron survival, not only during development, but also in the adult brain, thus raising the possibility that alterations in ionic currents could contribute actively to the demise of these neurons in Parkinson disease.
This review focuses on the mechanisms by which activity-dependent mechanisms might modulate dopaminergic cell survival.
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JOURNAL OF NEUROCHEMISTRY, Issue 3 2006Krishnan Sriram
Abstract
Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus.
A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation.
Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results.
Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1,, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-,.
Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection.
Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-, and its receptors, thereby failing to modulate TNF signaling.
Thus, TNF-, appeared to be an obligatory component of dopaminergic neurotoxicity.
To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2.
Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity.
However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP.
Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration.
These findings support the hypothesis that TNF-, may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.
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JOURNAL OF NEUROCHEMISTRY, Issue 4 2001J.-C. Liévens
There is growing evidence that the loss of the nigrostriatal dopaminergic neurones induces an overactivity of the corticostriatal glutamatergic pathway which seems to be central to the physiopathology of parkinsonism.
Moreover, glutamatergic mechanisms involving NMDA receptors have been shown to interfere with the therapeutical action of levodopa.
Given the key role played by uptake processes in glutamate neurotransmission, this study examined the effects of nigrostriatal deafferentation and of levodopa treatment on the striatal expression of the glutamate transporters GLT1, GLAST and EAAC1 in the rat.
No significant changes in striatal mRNA levels of these transporters were detected after either levodopa treatment (100 mg/kg; i.p., twice a day for 21 days) or unilateral lesion of the nigrostriatal pathway by intranigral 6-hydroxydopamine injection.
In contrast, animals with the lesion subsequently treated with levodopa showed a selective increase (36%) in GLT1 mRNA levels in the denervated striatum versus controls.
These animals also showed increased GLT1 protein expression, as assessed by immunostaining and western blotting.
These data provide the first evidence that levodopa therapy may interfere with striatal glutamate transmission through change in expression of the primarily glial glutamate transporter GLT1.
We further suggest that levodopa-induced GLT1 overexpression may represent a compensatory mechanism preventing neurotoxic accumulation of endogenous glutamate.
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